Wilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the copper transporting P-type ATPase gene ATP7B. Estimates for WD population prevalence vary with 1 in 30,000 generally quoted. However, some genetic studies have reported much higher prevalence rates. The aim of this study was to estimate the population prevalence of WD and the pathogenicity/penetrance of WD variants by determining the frequency of ATP7B variants in a genomic sequence database. A catalogue of WD-associated ATP7B variants was constructed, and then, frequency information for these was extracted from the gnomAD data set. Pathogenicity of variants was assessed by (a) comparing gnomAD allele frequencies against the number of reports for variants in the WD literature and (b) using variant effect prediction algorithms. 231 WD-associated ATP7B variants were identified in the gnomAD data set, giving an initial estimated population prevalence of around 1 in 2400. After exclusion of WD-associated ATP7B variants with predicted low penetrance, the revised estimate showed a prevalence of around 1 in 20,000, with higher rates in the Asian and Ashkenazi Jewish populations. Reanalysis of other recent genetic studies using our penetrance criteria also predicted lower population prevalences for WD in the UK and France than had been reported. Our results suggest that differences in variant penetrance can explain the discrepancy between reported epidemiological and genetic prevalences of WD. They also highlight the challenge in defining penetrance when assigning causality to some ATP7B variants.

威尔逊病（WD）是铜代谢的遗传疾病，是由铜转运P型ATPase基因ATP7B的变异引起的。WD人群患病率的估算值通常在30,000的人群中占1。但是，一些遗传学研究报告患病率更高。这项研究的目的是通过确定基因组序列数据库中ATP7B变体的频率来估计WD的种群流行度和WD变体的致病性/穿透性。WD相关的ATP7B目录构造变体，然后从gnomAD数据集中提取这些变体的频率信息。通过（a）将gnomAD等位基因频率与WD文献中有关变体的报告数量进行比较，以及（b）使用变体效应预测算法，评估变体的致病性。在gnomAD数据集中确定了231个与WD相关的ATP7B变体，从而初步估计种群患病率约为2400分之1。排除与WD相关的ATP7B预测的低渗透性的变种，修订后的估计显示患病率约为20,000分之一，在亚洲和阿什肯纳齐犹太人口中患病率更高。使用我们的出勤率标准对其他最近的遗传研究进行的重新分析还预测，英国和法国的WD人群患病率低于已报道的患病率。我们的结果表明，变异性外显率的差异可以解释WD的流行病学和遗传学患病率之间的差异。他们还强调了在将因果关系分配给某些ATP7B变体时定义外显率的挑战。